Background: Aldehyde dehydrogenase 2 (ALDH2) catalyzes the detoxification of aliphatic aldehydes, including acetaldehyde. About 45% of Han Chinese (East Asians), accounting for 8% of humans, carry a single point mutation in ALDH2*2 (E504K) that leads to accumulation of toxic reactive aldehydes. Methods: Sequencing of a small Mexican cohort and a search in the ExAC genomic database for additional ALDH2 variants common in various ethnic groups was set to identify missense variants. These were evaluated in vitro, and in cultured cells expressing these new and common variants. Findings: In a cohort of Hispanic donors, we identified 2 novel mutations in ALDH2. Using the ExAC genomic database, we found these identified variants and at least three other ALDH2 variants with a single point mutation among Latino, African, South Asian, and Finnish ethnic groups, at a frequency of >5/1000. Although located in different parts of the ALDH2 molecule, these common ALDH2 mutants exhibited a significant reduction in activity compared with the wild type enzyme in vitro and in 3T3 cells overexpressing each of the variants, and a greater ethanol-induced toxicity. As Alda-1, previously identified activator, did not activate some of the new mutant ALDH2 enzymes, we continued the screen and identified Alda-64, which is effective in correcting the loss of activity in most of these new and common ALDH2 variants. Interpretation: Since~80% of the world population consumes ethanol and since acetaldehyde accumulation contributes to a variety of diseases, the identification of additional inactivating variants of ALDH2 in different ethnic groups may help develop new 'precision medicine' for carriers of these inactive ALDH2.

BackgroundIt is well known that an early diagnosis and treatment for Rheumatoid Arthritis (RA) prevents its complications, therefore there are many efforts to identify individuals at risk to develop RA. The Squeeze test has been used to detect synovitis in metacarpophalangeal joints, even though it is used in daily practice, there is a great variability in their performance among rheumatologists. [2]ObjectivesThe aim of this study is to determine the diagnostic performance of the automated squeeze test (AST) on the metacarpophalangeal (MCP) joints to detect the presence of synovitis, edema, or erosions by magnetic resonance imaging (MRI) using the rheumatoid arthritis magnetic resonance imaging score (RAMRIS) in first-degree relatives (FDR) of RA patients, of whom clinically suspect arthralgia (CSA) in hands was suspected, as well as in RA patients.MethodsIt is an observational and cross-sectional study for a diagnostic test. A total of 60 patients, older than 18 years, were included and divided in three groups: CSA group: 22 with less than 1 year with arthralgia and required to be FDR of RA patients; early RA group: 22 patients who met ACR/EULAR 2010 Classification Criteria with less than 1 year with the disease; and late RA group: 16 patients who met ACR/EULAR 2010 Classification Criteria, with more than 1 year with the disease. The AST was performed in the 60 participants’ dominant hand. The device was evaluated by MRI, which examined the same hand in the 60 patients.ResultsA total of 240 MCP joints were evaluated. The AUC for the total RAMRIS score >10 was [0.480 (95% CI 0.301-0.617) P=0.597], for synovitis RAMRIS score > 7 was [0.459 (95% CI 0.331-0.669) P=0.791], and for the presence of any synovitis by RAMRIS was [0.575 (95% CI 0.428-0.723) P=0.331]. For the RAMRIS synovitis score, the most sensitive and specific cut-off of the force by AST was 4.645 kg with a 66.7% sensitivity and 50% specificity.Abstract AB1128 Table 1 Baseline characteristics TOTAL CSA n=22 ERA n=22 LRA n=16 Age mean (SD) 44.7 (13.7)37.6 (10.9)49.05 (11.9)47.5 (16.2) Female n (%) 50 (83.3)18 (81.8)18 (81.8)14 (87.5) TJC median (IQR) 4 (12)0.5 (4)5 (13)10 (11) SJC median (IQR) 3 (8)0 (3)5 (12)7.5 (9) DAS28-ESR median (IQR) 4.8 (1.5)5.4 (1.4) HAQ median (IQR) 0.64 (0.75)1.47 (0.94) CDAI median (IQR) 18.07(16.8)23.8 (15.5) Married n (%) 41 (68.3)12 (54.5)15 (71.4)14 (93.3) Smoker n (%) 19 (31.7)2 (22.7)10 (45.5)4 (25) Morning stiffness n (%) 31 (51.7)4 (18.2)16 (72.7)11 (68.8) RF IgM positivity n (%) 46 (76.7)9 (40.9)12 (70.6)4 (25) ACPA positivity n (%) 25 (41.7)19 (86.4)20 (90.9)7 (43.8)Clinically suspect arthralgia, CSA; Early Rheumatoid Arthritis, ERA; Late Rheumatoid Arthritis, LRA; Tender Joint Count, TJC; Swollen Joint Count, SJC; Disease Activity Score – Erythrocyte Sedimentation Rate, DAS28-ESR; Health Activity Questionnaire, HAQ; Clinical Disease Activity Index, CDAI; Rheumatoid Factor, RF; Anti-citrullinated peptides antibodies, ACPA.ConclusionThe application of AST with a force of 4.645 kg, to exert pain in the dominant hand...

Background:Clinically relevant anti-carbamylated (anti-CarP) antibodies are detected in up to 45% of rheumatoid arthritis (RA) patients and are associated with severe radiological progression, higher disease activity, and significantly more disability when studied in early phases of arthritis.Objectives:We aimed to determine the prevalence of anti-CarP antibodies in Mexican Hispanics with established RA and to assess their relationship with disease activity.Methods:A cohort study was conducted in 278 patients with established RA during an 18-month follow-up. We measured IgG/IgM/IgA rheumatoid factor (RF), IgG anticitrullinated protein antibodies (ACPA) and IgG/IgM/IgA anti-CarP antibodies using enzyme-linked immunosorbent assay (ELISA). For disease activity, we performed the 28-joint disease activity score with erythrocyte sedimentation rate (DAS28-ESR). Repeated measures one-way ANOVA was used to test the association between anti-CarP IgG antibody status and longitudinal DAS28-ESR scores. Patients were evaluated at baseline and at 6, 12, and 18 months during follow-up.Results:Anti-CarP IgG antibodies were positive in 47.8% of patients and, accounting for all isotypes, in 9.5% of patients with negative RF and ACPA. Triple antibody positivity was present in 42.6% of patients in our sample. Anti-CarP IgG antibody positivity did not show statistically significant differences in mean DAS28-ESR when compared to anti-CarP IgG antibody negative patients at baseline, 6, 12 or 18 months.Conclusion:Anti-CarP IgG antibodies are present in almost 50% of RA patients and, accounting for all isotypes, in 9% of RF and ACPA negative patients. Anti-CarP IgG antibody positivity was not associated to a higher disease activity measured by DAS28-ESR in Hispanic patients with established RA.References:Shi J, Knevel R, Suwannalai P, Van Der Linden MP, Janssen GMC, Van Veelen PA, et al. Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc Natl Acad Sci U S A. 2011;108:17372–17377.Table 1.Anti-CarP antibody status by isotype in a cohort of 278 patients with established RA.Mean (SD)Antibody positivity,n (%)95% CIRF IgAa266.9 (460.5)155 (58.9)53.0 to 64.9RF IgMa406.8 (611.9)188 (71.5)66.0 to 77.0RF IgGa36.1 (249.6)44 (16.7)12.2 to 21.3ACPA IgGa191.01 (411.1)144 (54.8)48.7 to 60.8Anti-CarP IgAb212.9 (464.2)74 (26.6)21.4 to 31.8Anti-CarP IgMb381.6 (762)89 (32)26.5 to 37.5Anti-CarP IgGb227.5 (402.5)133 (47.8)41.9 to 53.8aData were available for 263 patients. Units are RU/mL. bData were available for 278 patients. Units are AU/mL. RF, rheumatoid factor; ACPA, anticitrullinated protein antibodies; Anti-CarP, anti-carbamylated protein antibodies; IgG, immunoglobulin; SD, standard deviation; 95% CI, 95% confidence intervals.Figure 1.Disclosure of Interests:David Vega-Morales Grant/research support from: This research was funded as an Investigator Initiated Study by UCB (IIS-2015-104068). The sponsor did not have any role in the design or outcomes of this study., Mario Alberto Garza Elizondo: None declared, Leendert A Trouw: None declared, Karina Itzel González Márquez: None declared, Ernesto Torres-Lopez: None declared, Myriam Eguia Bernal: None declared, SALVADOR AZAHEL LOREDO ALANIS: None declared, Tayde Sarahi Gracia-Arechiga: None declared, Brenda Roxana Vázquez Fuentes: None declared, Diana Daniela Castañeda Martínez: None declared, Martha Mariana Castañeda-Martínez: None declared, Cesar Vidal Solis: None declared, Andres Mendiola-Jimenez: None declared, Mario Cesar Salinas-Carmona: None declared, Pablo Herrera-Sandate: None declared, Alberto Cárdenas: None declared, Gerardo Eugenio Rodriguez-Sanchez: None declared, Dionicio Ángel Galarza-Delgado: None declared